Since Ang II and ET-1 have a cell growth-accelerating action in addition to a blood pressure-elevating action, they are considered as causative agents or risk factors for diseases such as hypertension, hypercardia, cardiac infarction, arteriosclerosis, diabetic or non-diabetic renal diseases and restenosis after PTCA. Moreover, it is known that Ang II is formed from angiotensin I (hereinafter, abbreviated as Ang I) by angiotensin converting enzyme (hereinafter, abbreviated as ACE), and a large number of ACE inhibitors have been developed as agents for preventing or treating the above diseases. On the other hand, it is known that ET-1 is a physiologically active peptide composed of 21 amino acid residues (hereinafter, abbreviated as ET(1-21)) which is formed from big endothelin (hereinafter, abbreviated as Big ET-1) by endothelin converting enzyme (hereinafter, abbreviated as ECE), but ECE inhibitors and ET-1 receptor antagonists are still in developmental stages as medicaments.
Recently, in addition to ACE, an enzyme producing Ang. II from Ang I has been discovered and named chymase. Urata et al. purified chymase from human heart and has shown that 70 to 80% amount of Ang II produced in heart and blood vessels was due to chymase (J. Biol. Chem., 265, 22348 (1990). Moreover, when the fact that no effectiveness of ACE inhibitors on restenosis after PTCA is observed [MERCAPTOR, study (Circulation, 86 (1), 100 (1992)) and MARCAPTOR study (J. Am. Coll. Cardiol., 27(1), p. 1 (1996))] and the fact that chymase inhibitors are effective on a canine intimal thickening model of grafted blood vessel using jugular vein (Miyazaki, Takai et al.; Febs. Lett., 467, 141 (2000)) are together considered, it is important to inhibit chymase rather than ACE for preventing and treating cardiac and circulatory diseases and the like caused by abnormal increase of the production of Ang II, and thus the application of chymase inhibitors to cardiac and circulatory diseases is suggested.
Furthermore, in the recent past, it has been revealed that chymase specifically degrades Big ET-1 into a physiologically active peptide composed of 31 amino acid residues (hereinafter, abbreviated as ET(1-31)). It has been reported that the ET(1-31) acts on the receptor on which original ET(1-21) acts, to cause bronchoconstriction and vasoconstriction (Kido et al.; J. Immunol., 159, 1987 (1997)). In this connection, with regard to the concentration in human blood, both of ET(1-31) and ET(1-21) have about the same distribution and activity, and after cardiac infarction, ET(1-31) increases more largely than ET(1-21) does, which is maintained for two weeks after the incidence (Tamaki, Nishistu et al.; Jpn. J. Pharmacol., 82(suppl I), 26 (2000)), and the fact suggests importance of inhibition of chymase and application of chymase inhibitors to cardiac and circulatory diseases.
Accordingly, chymase is considered to participate in production and degradation of physiologically active peptides, remodeling of extracellular matrix, network with cytokine, immunity, and the like and contribute to restoration of metabolic turnover. Thus, a chymase inhibitor is expected to apply to cardiac and circulatory diseases.
Moreover, as a result of administration of Ang II into a sponge in a hamster subdermally sponge-implanted model, removal of the sponge after 7 days, and measurement of hemoglobin content, vascularization was observed (mainly capillary vessels). When ovalbumin (10 μg/site/day) as an antigen is administered to a sensitized animal via sponge, vascularization occurs as in the case of Compound 48/80. This vascularization was also inhibited by chymostatin (Muramatsu et al.; J. Biol. Chem., 275(8), 5545 (2000)). The above results indicate that activation of mast cells by antigen stimulation can also cause vascularization, and chymase may be involved in this process. Thus, new roles of chymase are suggested in a variety of inflammatory allergy diseases. From such a viewpoint, a chymase inhibitor is expected to exhibit effects on solid tumors, diabetic retinopathy, rheumatoid arthritis and atherosclerosis.
Currently, as inhibitors against chymase, peptide-type chymase inhibitors are disclosed in JP-A-1D-7661, JP-A-11-49739, JP-A-11-246437, WO98/09949, WO98/18794, WO99/45928, WO99/32459 and WO00/06594. On the other hand, non-peptide-type chymase inhibitors are disclosed in JP-A-10-8749-3, JP-A-10-245384, JP-A-12-95770, WO96/04248, WO97/11941, WO99/09977, WO00/03997, WO00/05204, WO00/10982, WO00/32587, WO01/32214, WO01/32621 and WO01/83471. However, until now, no clinically applicable chymase inhibitor has been found. Accordingly, it is desired to develop a clinically applicable, chymase inhibitor which enables prevention and treatment of cardiac and circulatory diseases and the like caused by abnormal increase of production of Ang II and ET-1, or by activation of mast cell.
Pulmonary hypertension as above is a pathological condition in which the average blood pressure of pulmonary artery is increased (25 mmHg or more) at rest through elevation of pulmonary vascular resistance and which may result in an after effect of hemodynamic change which is a possible danger to life. Slight physical exertion develops symptoms such as shortness of breath breathing difficulty, fatigue, spasm of vertigo and loss of consciousness. In particular, pulmonary hypertension whose cause is unknown is called primary pulmonary hypertension, which breaks out with a frequency of 1 to 3 persons per 1 million persons and is a disease of a very bad prognosis, average survival time being 3 to 5 years from its diagnosis.
As a treatment for pulmonary hypertension, a therapy of constant intravenous infusion of a prostacyclin injection is introduced and shows a therapeutic effect (N. Engl. J. Med., 334, 296 (1996)). However, since a drug solution is constantly infused in this therapy, it is necessary to indwell a central venous catheter and carry a pump and hence the therapy imposes a heavy burden on patients and troubles such as infection at a catheter inserted part may sometimes occur. Moreover, a therapy of inhalation of nitrogen monoxide (NO) is effective for selective pulmonary vasodilation and is an indispensable therapy at the treatment of pulmonary hypertension in intensive care field, but the therapy requires a large-scale exclusive instrument as well as there are a lot of points to be improved in view of safety management (Nihon Rinsho, 59, 1126 (2001)).
In addition, application to pulmonary hypertension is investigated using a pharmaceutical agent such as an endothelin receptor blocker, a phosphodiesterase inhibitor, a thromboxane synthesis inhibitor or an angiotensin II receptor blocker. However, these agents are not used clinically because they exhibit insufficient effect or adverse effect for example, most of them cause systemic blood-pressure decrease (Nihon Rinsho, 59, 1139 (2001)).
There is a report that chymase-containing mast cells are accumulated in the lung tissue and pulmonary artery of pulmonary hypertension patients (Am. J. Respir. Crit. Care. Med., 160, 1303 (1999), Thorax., 54, 88 (1999)), and chymase released from the mast cells accumulated in the lung is considered to be one cause of thickening of vascular tunica media. Moreover, there is a suggestion that an acylsulfonamide derivative which is a chymase inhibitor may be an agent for treating or preventing pulmonary hypertension (JP-A-2001-97946). However, there is no report that a specific chymase inhibitor is actually effective for preventing or treating pulmonary hypertension.
Furthermore, a tissue adhesion in the body of mammals including human occurs after surgery in clinical fields such as gastroenterology, cardiology, orthopedics, gynecology and ophthalmology and exerts a strong influence on prognosis together with pain in patients. For example, in the case of abdominal operation, there arises a phenomenon that intraperitoneal organs such as abdominal wall and intestinal tracts mutually adhere after the operation, which sometimes causes ileus. In some cases, re-operation is required. In gynecological field, postoperative adhesion occurs in the patients who had an infection operation or intrapelvic operation, and sometimes causes sterility through tubal blockage. Also in cardiosurgery field, there is a case that re-operation is restricted by adhesion or there is a possible problem of bleeding at re-operation. In ophthalmic region, it becomes difficult to maintain quality of vision including insufficient control of intraocular pressure when organic adhesion or postoperative adhesion occurs.
As a prevention of postoperative adhesion, there are attempts to employ a variety of pharmaceutical agents or special films. As the pharmaceutical agents for preventing adhesion, there may be mentioned high-molecular weight polysaccharides having a wound surface-covering action such as sodium alginate, sodium chondroitin sulfate, high-molecular weight dextran and sodium hyaluronate. As agents for preventing postoperative adhesion of tubal orthosis, glucocorticoids such as dexamethasone and triamcinolone acetonide are employed. As films, films or sponges using gelatin (Gelfilm, Gelfoam (registered trademarks)), polytetrafluoroethylene sheets (Gore-Tex (registered trademark)) and hyaluronic acid sheets modified with carboxymethyl cellulose or the like (Seprafilm (registered trademark)) are employed. However, any agents are not satisfactory in view of the effects.
In this regard, recently, there are reported that a peptide Suc-Val-Pro-PheP(OPh)2 which is a chymase inhibitor suppresses adhesion of organs after rubbing the uterus of a hamster adhesion model (Eur. J. Pharmacol., 435, 265 (2002)) and also adhesion at filtering blebs in a canine trabeculectomy model (Nihon Ganka gakkai Zasshi, Vol. 106, (extra number), 131 (2002)). In addition, it is suggested that a chymase inhibitor which is a quinazoline derivative can be utilized for preventing postoperative adhesion through alleviation of extracellular matrix dysbolism (WO01/62292).